Cyclohexanone-1,3-diones play an important role in organic synthesis due to their usefulness in the preparation of many biological important compounds. Cyclohexane-1,3-diones refer to an important class of compounds known for their herbicidal activity and anti-inflammatory activity. Cyclohexane-1,3-diols are useful building blocks in pharmaceuticals, and can be easily prepared from cyclohexane-1,3-dione derivatives (Leijondahal, K.; Fransson, A. L.; Backvall, J. J. Org. Chem. 2006, 71, 8622-8625). 2-(substituted)-1,3-cyclohexanedione (Cain, P. A.; Cramp, S. M. European Patent E0496630) such as NTBC is a triketone with herbicidal activity i.e. potent inhibitor of enzyme 4-hydroxyphenyl pyruvate dioxygenase (HPPD) in plants and developed as drug to cure children with a rare inborn error of metabolism (Lock, E; A.; Ellis, M. K.; Gaskin, P.; Robinson, M.; Auton, T. R.; Provan, W. M.; Smith, L. L; Prisbylla, M. P.; Mutter, L. C.; Lee, D. L. J. Inher. Metab. Dis. 1998, 21, 498-506).
The known polyketides, surinone A and oleiferinone, showed growth inhibitory activity against the WI-138, VA-13, and HepG2 cell lines with IC50 values that ranged from 4.4 to 9.6 micro g/ml (Li, N.; Wu, j.; Hasegawa, T.; Sakai, J.; Bai, L.; Wang, L.; Kakuta, S.; Furuya, Y.; Ogura, H.; Kataoka, T.; Tomida, A.; Tsuruo, T.; Ando, M. J. Nat. Prod. 2007, 70, 998-1001). Humphrey et al. used cyclohexane-1,3-dione (CHD) resin as a solid support for synthesis of amides (Humphrey, C. E.; Easson, M. A. M.; Tierney, J. P.; Turner. N. J. Org. Lett. 2002, 5, 849-852).
Although several methods have been reported for the synthesis of cyclohexane-1,3-dione derivatives (Ryu, E. K.; Kim, K. M.; Kim, H. R.; Song, J. H.; Kim, J. N.; Kim, J. S. WO/1994/003443) but these methods are lengthy, laborious, time consuming and costly. Few reactions have been published, where acetone under KF-Alumina basic condition gives double Michael product (Basu, B.; Das, P.; Hossain, I. Synlett 2004, 12, 2224-2226) and acetone derivatives under t-BuOK condition gives cyclized products with quaternary carbon at C-4 position (Ishikawa, T.; Kadoya, R.; Arai, M.; Takahash, H.; Kaisi, Y.; Mizuta, T.; Yoshikai, K.; Satio, S. J. Org. Chem. 2001, 66, 8000-8009).
Few studies have been reported for the synthesis of cyclohexane-1,3-dione derivatives using acetone derivatives. Reactions of substituted acetone derivatives in the presence of t-BuOK (200 mol %) in t-BuOH-THF condition performed double Michael and Claisen reaction to produce 4,4-disubstituted cyclohexane-1,3-diones (Ishikawa, T.; Kudo, K.; Kuroyabu, K.; Uchida, S.; Kudoh, T.; Saito, S. J. Org. Chem. 2008, 73, 7498-7508). Cyclohexane-1,3-dione derivatives and their herbicidal activities were already known in the art. For example, Alloxidim-sodium (Sawaki, M.; Iwataki, I.; Hirono, Y.; Ishikawa, H. U.S. Pat. No. 3,950,420) and Sethoxidim (Somers, D. A.; Parker, W. B.; Wyse, D. L. Gronwald, J. W.; Gengenbach, B. G. U.S. Pat. No. 5,162,602, Johnson, M. D.; Dunne, C. L.; Kidder, D. W.; Hudetz, M. EP19970953744) have come into the market as grass herbicides. Cyclohexane-1,3-dione derivatives having phenyl substituent (Serban, A.; Watson, K. G.; Bird, G. J.; Farquharson, G. J. U.S. Pat. No. 4,511,391, Farquharson; G. J.; Watson; K. G.; Bird; G. J. U.S. Pat. No. 4,639,267 and Watson, K. G.; Bird, G. J.; Farquharson, G. J. U.S. Pat. No. 4,652,303) which have structural similarities to our invention. 5-(hetero-substituted) cyclohexane-1,3-dione derivatives have herbicidal as well as plant growth regulating properties (Conway, R. J.; Watson, K. G.; Farquharson, G. J. U.S. Pat. No. 4,604,132). 5-substituted cyclohexane-1,3-dione derivatives act as herbicide for the selective control of undesirable grasses in broad-leaved crops (Jahn, D.; Rohr, W.; Becker, R.; Wuerzer, B).
References may be made to U.S. Pat. No. 4,844,735, wherein Mesotione i.e. 2-(4-methylsulfonyl-2-nitrobenzoyl)-1,3-cyclohexanedione is a new selective, pre and post emergent herbicide for control of broad-leaved and some grass weeds in corn is reported. This compound acts by competitive inhibition of the enzyme 4-hydroxy phenyl pyruvate dioxygenase (HPPD) which affects carotenoid biosynthesis ((a) Alferness, P.; Wiebe, L. J. Agric. Food Chem. 2002, 50, 3926-3934; (b) Mitchell, G.; Bartlett, D. W.; Fraser, T. E.; Hawkes, T. R.; Holt, D. C.; Townson, J. K.; Wichert, R. A. Pest. Manage. Sci. 2001, 57, 120-128).
A new Cyclohexane-1,3-dione derivative, EK-2612 shows grass killer herbicidal activity specially in monocotyledons plants like rice and barnyard grass (Kim, T. J.; Kim, J. S.; Hong, K. S.; Hwang, I. T.; Kim, K. M.; Kim, H. R.; Cho, K. Y. Pest. Manage. Sci. 2004, 60, 909-913).
4-Hydroxy-2-substituted-Cyclohexane-1,3-dione i.e. polyketides are responsible for cytotoxic and anti-inflammatory bioactivities (Li, N.; Wu, J. L.; Hasegawa, T.; Sakai, J. I.; Bai, L. M.; Wang, L. Y.; Kakuta, S.; Furuya, Y.; Ogura, H.; Kataoka, T.; Tomida, A.; Tsuruo, T.; Ando, M. J. Nat. Prod. 2007, 70, 998-1001).
2-substituted-Cyclohexane-1,3-diones are attractive intermediates in the synthesis of natural products and in medicinal chemistry as well as pharmaceutical chemistry. They are also excellent starting materials in the natural product synthesis ((a) Gardner, J. N.; Anderson, B. A.; Oliveto, E. P. J. Org. Chem. 1969, 34, 107-111. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496-497. (c) Newkome, G. R.; Roach, L. C.; Montelaro, R. C. J. Org. Chem. 1972, 37, 2098-2101. (d) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239-3243).
Wieland-Miescher (W-M) ketone analogue are very good intermediates for the synthesis of steroids. W-M ketone analogue is very substantial intermediate for the synthesis of pharmaceutically acceptable salts or hydrates of spiro-heterocycles, which are disclosed as selective glucocorticoid receptor modulators for treating a variety of autoimmune and inflammatory diseases or conditions (Ali, A.; Balkovec, J. M.; Beresis, R.; Colletti, S. L.; Graham, D. W.; Patel, G. F.; Smith, C. WO/2004/093805).
Cyclohexane-1,3-dione derivatives are main building block for substituted aromatic compounds synthesis. Aromatization of cyclohexane-1,3-dione derivatives have been performed using several conditions but most successful results have been observed under iodine in methanol (Kim, J. M.; Lee, K. Y.; Kim, J. N. Bull. Korean Chem. Soc. 2003, 24 (8), 1057-1058). To the best of our knowledge, we have developed a novel protocol for the synthesis of cyclohexane-1,3-diones not related with any methods described in above examples. Further functionalization strategies have been applied for the synthesis of several other molecules having novel structural moiety such as enaminone derivatives of cyclohexane-1,3-dione.
By using acetone, Aldol reaction was widely modified. But not a single report has been published in literature for the synthesis of such a versatile intermediate cyclohexane-1,3-dione derivatives useful in several value added organic molecules synthesis.
In summary, first time we have developed a new protocol for the synthesis of 3-(2,4-cyclohexanone)-propyl carboxylic acid ethyl ester 3 starting from acetone and ethyl acrylate in one-pot reaction. Compound 3 works as a versatile intermediate in several bioactive, value added organic molecules and natural products analogue synthesis.